Throughout this disclosure, various publications, patents and patent applications are referenced. The disclosures of these publications, patents and patent applications are herein incorporated by reference
This invention relates to an improved therapy for treating patients having chronic myelocytic leukemia (xe2x80x9cCMLxe2x80x9d) by administering a therapeutically effective dose of pegylated interferon-alpha for a time sufficient to achieve at least a partial cytogenetic response.
Guilhot, F. et al. disclosed in N. Engl. J. Med., 1997, Volume 337, pages 223-229 that the combination of interferon alpha-2b and cytarabine increased the rate of major cytogenetic response and prolonged survival in patients in the chronic phase of CML. It must be noted that daily injections of interferon alpha-2b were required to achieve these results. In addition, interferon alpha-2b has many side effects that a substantial number of patients find unacceptable, and patient compliance with the daily injections of interferon alpha-2b has become a problem. Allogenic bone marrow transplantation (xe2x80x9cBMTxe2x80x9d) may be an alternative for CML patients with HLA-identical siblings. However, many patients are clearly too old or lack suitable donors and thus BMT is ruled out for most of these patients. (See the Editorial by Goldman, John M. in N. Engl. J. Med. 1997 volume 337, pages 270-271.) Accordingly, there is a need for an improved therapy for treating patients having CML.
The present invention provides a method of treating a patient having chronic myelogenous leukemia which comprises administering to such a patient a therapeutically effective dose of pegylated interferon alpha for a time period sufficient to effect at least a partial cytogenetic response.
The present invention also provides a method of treating a patient having chronic phase chronic myelogenous leukemia which comprises administering to said patient an effective amount of pegylated interferon-alpha once a week for a time period sufficient to effect at least a partial cytogenetic response.
The present invention further provides a method of a patient having chronic phase of chronic myelogenous leukemia which comprises administering to such a patient about 4.5 micrograms/kg to about 9.0 micrograms/kg of pegylated interferon alpha-2b once a week for a time period sufficient to effect at least a partial cytogenetic response.
The present invention provides an improved method of treating patients with CML-especially those in the chronic phase of CML. The improved method provides a safer and more efficacious and tolerable treatment for CML by use of weekly injections of pegylated interferon alpha alone or in combination with chemotherapeutic agents such as cytarabine. The CML patients include those newly diagnosed with this disease as well as those patients intolerant or resistant to interferon alpha. Normally, hydroxyurea is given as needed to the CML patients before initiation of the method of the present invention to reduce the leukocyte count. Treatment with pegylated interferon alpha in accordance with the present invention will continue for a minimum of six months, and preferably for at least twelve months unless there is clinical evidence of disease progression, unacceptable toxicity or the patient requests that the therapy be discontinued.
When the pegylated interferon-alpha administered is a pegylated interferon alpha-2b, the therapeutically effective amount of pegylated interferon alpha-2b administered is in the range of about 4.5 to about 9.0 micrograms per kilogram of pegylated interferon alpha-2b administered once a week (QW), preferably about 4.5 to about 6.5 micrograms per kilogram of pegylated interferon alpha-2b administered once a week, more preferably about 5.5 to about 6.5 micrograms per kilogram of pegylated interferon alpha-2b administered once a week, and most preferably about 6.0 micrograms per kilogram of pegylated interferon alpha-2b administered once a week.
When the pegylated interferon-alpha administered is a pegylated interferon alpha-2a, the therapeutically effective amount of pegylated interferon alpha-2a administered is in the range of about 50 micrograms to about 500 micrograms once a week(xe2x80x9cQWxe2x80x9d), preferably about 200 micrograms to about 250 micrograms QW.
The term xe2x80x9cpegylated interferon alphaxe2x80x9d as used herein means polyethylene glycol modified conjugates of interferon alpha, preferably interferon alpha-2a and -2b. The preferred polyethylene-glycol-interferon alpha-2b conjugate is PEG12000-interferon alpha 2b. The phrases xe2x80x9c12,000 molecular weight polyethylene glycol conjugated interferon alphaxe2x80x9d and xe2x80x9cPEG12000-IFN alphaxe2x80x9d as used herein mean conjugates such as are prepared according to the methods of International Application No. WO 95/13090 and containing urethane linkages between the interferon alpha-2a or -2b amino groups and polyethylene glycol having an average molecular weight of 12000.
The preferred PEG12000-interferon alpha-2b is prepared by attaching a PEG polymer to the epsilon amino group of a lysine residue in the IFN alpha-2b molecule. A single PEG12000 molecule is conjugated to free amino groups on an IFN alpha-2b molecule via a urethane linkage. This conjugate is characterized by the molecular weight of PEG12000 attached. The PEG12000-IFN alpha-2b conjugate is formulated as a lyophilized powder for injection. The objective of conjugation of IFN alpha with PEG is to improve the delivery of the protein by significantly prolonging its plasma half-life, and thereby provide protracted activity of IFN alpha.
The term xe2x80x9cinterferon-alphaxe2x80x9d as used herein means the family of highly homologous species-specific proteins that inhibit viral replication and cellular proliferation and modulate immune response. Typical suitable interferon-alphas include, but are not limited to, recombinant interferon alpha-2b such as Intron-A interferon available from Schering Corporation, Kenilworth, N.J., recombinant interferon alpha-2a such as Roferon interferon available from Hoffmann-La Roche, Nutley, N.J., recombinant interferon alpha-2C such as Berofor alpha 2 interferon available from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, Conn., interferon alpha-n1, a purified blend of natural alpha interferons such as Sumiferon available from Sumitomo, Japan or as Wellferon interferon alpha-n1 (INS) available from the Glaxo-Wellcome Ltd., London, Great Britain, or a consensus alpha interferon such as those described in U.S. Pat. Nos. 4,897,471 and 4,695,623 (especially Examples 7, 8 or 9 thereof) and the specific product available from Amgen, Inc., Newbury Park, Calif., or interferon alpha-n3 a mixture of natural alpha interferons made by Interferon Sciences and available from the Purdue Frederick Co., Norwalk, Conn., under the Alferon Tradename. The use of interferon alpha-2a or alpha-2b is preferred. Since interferon alpha-2b, among all interferons, has the broadest approval throughout the world for treating chronic hepatitis C infection, it is most preferred. The manufacture of interferon alpha-2b is described in U.S. Pat. No. 4,530,901.
Other interferon alpha conjugates can be prepared by coupling an interferon alpha to a water-soluble polymer. A non-limiting list of such polymers include other polyalkylene oxide homopolymers such as polypropylene glycols, polyoxyethylenated polyols, copolymers thereof and block copolymers thereof. As an alternative to polyalkylene oxide-based polymers, effectively non-antigenic materials such as dextran, polyvinylpyrrolidones, polyacrylamides, polyvinyl alcohols, carbohydrate-based polymers and the like can be used. Such interferon alpha-polymer conjugates are described in U.S. Pat. No. 4,766,106, U.S. Pat. No. 4,917,888, European Patent Application No. 0 236 987, European Patent Application Nos. 0 510 356, 0 593 868 and 0 809 996(pegylated interferon alpha-2a) and International Publication No. WO 95/13090.
Pharmaceutical composition of pegylated interferon alpha-suitable for parenteral administration may be formulated with a suitable buffer, e.g., Tris-HCl, acetate or phosphate such as dibasic sodium phosphate/monobasic sodium phosphate buffer, and pharmaceutically acceptable excipients (e.g., sucrose), carriers (e.g. human serum albumin), toxicity agents (e.g. NaCl), preservatives (e.g. thimerosol, cresol or benylalcohol), and surfactants (e.g. tween or polysorabates) in sterile water for injection. The pegylated interferon alpha-may be stored as lyophilized powders under a refrigeration at 2xc2x0-8xc2x0 C. The reconstituted aqueous solutions are stable when stored between 20xc2x0 and 8xc2x0 C. and used within 24 hours of reconstitution. See for example U.S. Pat. Nos. 4,492,537; 5,762,923 and 5,766,582. The reconstituted aqueous solutions may also be stored in prefilled, multi-dose syringes such as those useful for delivery of drugs such as insulin. Typical suitable syringes include systems comprising a prefilled vial attached to a pen-type syringe such as the NOVOLET Novo Pen available from Novo Nordisk, as well as prefilled, pen-type syringes which allow easy self-injection by the user. Other syringe systems include a pen-type syringe comprising a glass cartridge containing a diluent and lyophilized pegylated interferon alpha powder in a separate compartment.
CML (chronic myelogenous leukemia) is a clonal myeloproliferative disorder which is a neoplastic proliferation of the pluripotential stem cell. In CML, the leukemic cells retain some ability to differentiate. Hence, at the time CML is diagnosed, the white cell count in CML may range from 10,000 to  greater than 200,000 cells/mm3 with 90% of the cells in the granulocyte series. Hematocrit, hemoglobin and platelet counts are usually normal although the platelet count and number of basophils may be increased. CML was the first cancer to be associated with a specific cytogenetic abnormality, the Philadelphia chromosome (Ph1), a reciprocal translocation involving chromosomes 22 and 9. A segment of the long arm of chromosome 9 which contains the c-abl oncogene is translocated to the q11 position on chromosome 22 within a specified segment designated as the breakpoint cluster region (bcr). This results in a new gene, bcr/abl, on chromosome 22 within an associated abnormal messenger RNA, which can be detected by RT-PCR (reverse transcriptase polymerase chain reaction), and an abnormal protein product. A bcr/abl gene rearrangement is the major pathogenic mechanism underlying the development of CML.
The term xe2x80x9ccytogenic responsexe2x80x9d as used herein means a reduction or elimination of Philadelphia chromosone-positive cells (xe2x80x9cPh1+cellsxe2x80x9d) in the bone marrow. A complete cytogenetic response means there are no Ph1+cells; a major cytogenetic response means there are about 1 to about 34% of such cells i.e.  less than about 35% Ph1+cells. Minor response means about 35 to about 90% of such cells and treatment failure about 91 to about 100% of such cells i.e.,  greater than about 90% Ph1+cells). Clinicans have suggested that achievement of a major cytogenic response i.e.  less than about 35% of Ph+cells in the bone marrow after 1 year of CML therapy is predictive of long-term survival.
The term xe2x80x9cpatients having chronic myelogenous leukemia or CMLxe2x80x9d as used herein means any patient having CML and includes treatment-naive patients as well as treatment-experienced patients as well as patients in the chronic phase of CML.
The term xe2x80x9ctreatment-naive patientsxe2x80x9d as used herein means patients with CMLxe2x80x94including newly-diagnosed CML patientsxe2x80x94who have never been treated with any chemotherapeutic drugs, including but not limited to, e.g., busulfan(xe2x80x9cBUxe2x80x9d), hydroxyurea(xe2x80x9cHUxe2x80x9d), Homoharringtonine (xe2x80x9cHHTxe2x80x9d), cytarabine(xe2x80x9cAra-Cxe2x80x9d), Idadubicin(xe2x80x9cIxe2x80x9d), Etoposide(xe2x80x9cExe2x80x9d) or chemotherapeutic drug combinations, e.g., 1+Ara-C+E, i.e., xe2x80x9cICExe2x80x9d as well as any interferon, including but not limited to interferon alpha, or pegylated interferon alpha.
The term xe2x80x9ctreatment-experienced patients as used herein means those patients who have initiated some form of chemotherapeutic drug therapy including, but not limited to chemotherapeutic drug, e.g., busulfan(xe2x80x9cBUxe2x80x9d), hydroxyurea(xe2x80x9cHUxe2x80x9d), Homoharringtonine (xe2x80x9cHHTxe2x80x9d), cytarabine(xe2x80x9cAra-Cxe2x80x9d), Idadubicin(xe2x80x9cIxe2x80x9d), Etoposide(xe2x80x9cExe2x80x9d) or chemotherapeutic drug combinations, e.g., xe2x80x9cICExe2x80x9d.
The term xe2x80x9chematologic responsexe2x80x9d as used herein means an improvement in the WBC, and platelets.
A complete hematologic response means a WBC of less than 10,000 per microliter and a platelet count of less than 450,000 per microliter and normal differential in peripheral blood, and no palpable spleen.
A partial hematologic response means a WBC of fewer than about 20,000 per microliter, or at least about a 50% reduction in the WBC baseline (measured pretreatment).
In a preferred embodiment of the present invention, hydroxyurea is administered to CML patients prior to initiation of pegylated interferon alpha, and preferably about two weeks up to about three months prior to initiation of pegylated interferon alpha.
Pegylated interferon-alpha formulations are not effective when administered orally, so the preferred method of administering the pegylated interferon-alpha is parenterally, preferably by subcutaneous, IV, or IM, injection. Of course, other types of administration of both medicaments, as they become available are contemplated, such as by nasal spray, transdermally, by suppository, by sustained release dosage form, and by pulmonary inhalation. Any form of administration will work so long as the proper dosages are delivered without destroying the active ingredient.